Tubulointerstitial fibrosis, a common endpoint outcome of a wide range of chronic kidney diseases (CKD), is preceded by activation of the a-smooth muscle actin-positive myofibroblasts, the principal effector cells that are responsible for the over-production of extracellular matrix components. This is the A1 revision of a R01 competitive renewal application, which proposes to continue our long- term efforts to elucidate the origins, activation and regulation of myofibroblasts in renal fibrogenesis. Studies in previous project period of this application indicate that dysregulated activation of key developmental signaling such as sonic hedgehog (Shh) and Wnt/beta-catenin plays a critical role in mediating fibroblast activation and renal fibrosis. In this renewal application, studies are designed to testa central hypothesis that Shh and Wnts mediate a two-way cross-talk between tubular epithelium and interstitial fibroblasts, and such 'epithelial-mesenchymal communication (EMC)'plays an essential role in promoting fibroblast activation and matrix production. The entire application consists of three specific aims. Aim 1 is to investigate the role of tubule-derived Shh in promoting fibroblast proliferation and activation. Aim 2 is to investigate the role of fibroblast-derived Wnts in mediating the fibrogenic responses of tubular epithelium. Aim 3 is to investigate the therapeutic effects of blocking Shh or/and Wnt signaling with small molecule inhibitors or endogenous antagonist on renal fibrosis. These studies promise to offer important insights into understanding how tubular injury in diseased kidneys drives fibroblast proliferation and activation, leading to excessive matrix production and scar formation. Undoubtedly, the data generated from this application will have wide implications in comprehending the pathogenesis of renal fibrosis after injury, as well as in designing future therapeutic regimens for treatment.

Public Health Relevance

It is estimated that up to 13% of the US adult population has some degree of chronic kidney disease (CKD), characterized by kidney function decline and tissue fibrosis. CKD often progresses into end- stage renal failure, a devastating condition requiring renal replacement therapy. The studies proposed in this application promises to provide important insights into understanding the patho-mechanism of renal fibrosis, and may offer unique opportunities for designing rational strategies for the treatment of human fibrotic CKD.